Project Summary Despite substantial progress in the development of medications to lower pulmonary vascular resistance in pulmonary arterial hypertension (PAH), there are no therapies that are known to benefit the right heart in the absence of changes in right ventricular afterload. Right heart failure is the key driver for morbidity and mortality in patients with PAH, but also complicates a range of other common diseases such as emphysema and left heart failure. We are currently enrolling participants in an NHLBI sponsored, Phase 2, single-center, randomized placebo controlled trial of famotidine (an H2 receptor antagonist) as a novel therapeutic for adults with PAH. The study is evaluating the ability of a 24-week course of famotidine to stabilize right heart failure. Study end-points include six-minute walk distance, right ventricular function and dilation, biochemical markers of right heart failure (nt-pro-BNP), New York Heart Association Functional Class, and health related quality of life as assessed by the disease specific emPHasis-10 instrument. The primary goal of this application is to leverage samples from our ongoing clinical trial to undertake a multi-omics and systems biology approach to elucidate the biology of this unique cohort with right heart failure. The current proposal is designed to better understand the biologic impact of modulating histaminic signaling, define the multi-omics profiles of individuals with right heart failure who are likely to respond to H2 receptor antagonists, and to discover activated pathways distinguishing individuals with stable right heart function from those with worsening right heart failure. Our previous work strongly implicates an important role for histaminic signaling in right heart failure and we have generated exciting preliminary data showing that omics-based characterization can identify clinically relevant phenotypes in patients with PAH. The current proposal is well aligned with the NHLBI strategic vision to prioritize a deeper understanding of biology in diseases of the heart, lung, and blood through the integration of multi- omics data and discrete clinical phenotypes. This goal is particularly important in the current proposal given the burden of right heart failure across a range of distinct diseases and the lack of effective medications that promote right heart adaptation over failure. The proximate goal of enhancing our understanding of histaminic signaling in right heart failure promises short to intermediate-term clinical deliverables given the number of well-tolerated, inexpensive medications targeting this pathway.